4gh6

From Proteopedia

(Difference between revisions)

Revision as of 06:56, 26 October 2022

Crystal structure of the PDE9A catalytic domain in complex with inhibitor 28

Structural highlights

4gh6 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PDE9A_HUMAN Hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.^[1]

Publication Abstract from PubMed

A new series of phosphodiesterase-9 (PDE9) inhibitors that contain a scaffold of 6-amino-pyrazolopyrimidinone have been discovered by a combination of structure-based design and computational docking. This procedure significantly saved the load of chemical synthesis and is an effective method for the discovery of inhibitors. The best compound 28 has an IC(50) of 21 nM and 3.3 muM, respectively, for PDE9 and PDE5 and about 3 orders of magnitude of selectivity against other PDE families. The crystal structure of the PDE9 catalytic domain in complex with 28 has been determined and shows a hydrogen bond between 28 and Tyr424. This hydrogen bond may account for the 860-fold selectivity of 28 against PDE1B, in comparison with about 30-fold selectivity of BAY73-6691. Thus, our studies suggest that Tyr424, a unique residue of PDE8 and PDE9, is a potential target for improvement of selectivity of PDE9 inhibitors.

Structure-Based Discovery of Highly Selective Phosphodiesterase-9A Inhibitors and Implications for Inhibitor Design.,Meng F, Hou J, Shao YX, Wu PY, Huang M, Zhu X, Cai Y, Li Z, Xu J, Liu P, Luo HB, Wan Y, Ke H J Med Chem. 2012 Oct 1. PMID:22985069^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Liu S, Mansour MN, Dillman KS, Perez JR, Danley DE, Aeed PA, Simons SP, Lemotte PK, Menniti FS. Structural basis for the catalytic mechanism of human phosphodiesterase 9. Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13309-14. Epub 2008 Aug 29. PMID:18757755
↑ Meng F, Hou J, Shao YX, Wu PY, Huang M, Zhu X, Cai Y, Li Z, Xu J, Liu P, Luo HB, Wan Y, Ke H. Structure-Based Discovery of Highly Selective Phosphodiesterase-9A Inhibitors and Implications for Inhibitor Design. J Med Chem. 2012 Oct 1. PMID:22985069 doi:http://dx.doi.org/10.1021/jm301189c

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4gh6"

Categories: Homo sapiens | Large Structures | Hou J | Ke H

@@ Line 1: / Line 1: @@
 ==Crystal structure of the PDE9A catalytic domain in complex with inhibitor 28==
-<StructureSection load='4gh6' size='340' side='right' caption='[[4gh6]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
+<StructureSection load='4gh6' size='340' side='right'caption='[[4gh6]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4gh6]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GH6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4GH6 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4gh6]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4GH6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4GH6 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LUO:N-(4-METHOXYPHENYL)-N~2~-[1-(2-METHYLPHENYL)-4-OXO-4,5-DIHYDRO-1H-PYRAZOLO[3,4-D]PYRIMIDIN-6-YL]-L-ALANINAMIDE'>LUO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LUO:N-(4-METHOXYPHENYL)-N~2~-[1-(2-METHYLPHENYL)-4-OXO-4,5-DIHYDRO-1H-PYRAZOLO[3,4-D]PYRIMIDIN-6-YL]-L-ALANINAMIDE'>LUO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE9A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4gh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gh6 OCA], [https://pdbe.org/4gh6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4gh6 RCSB], [https://www.ebi.ac.uk/pdbsum/4gh6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4gh6 ProSAT]</span></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/3',5'-cyclic-GMP_phosphodiesterase 3',5'-cyclic-GMP phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.35 3.1.4.35] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4gh6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4gh6 OCA], [http://pdbe.org/4gh6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4gh6 RCSB], [http://www.ebi.ac.uk/pdbsum/4gh6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4gh6 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/PDE9A_HUMAN PDE9A_HUMAN]] Hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.<ref>PMID:18757755</ref>
+[https://www.uniprot.org/uniprot/PDE9A_HUMAN PDE9A_HUMAN] Hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.<ref>PMID:18757755</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 20: @@
 ==See Also==
-*[[Phosphodiesterase|Phosphodiesterase]]
+*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: 3',5'-cyclic-GMP phosphodiesterase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
+[[Category: Large Structures]]
-[[Category: Hou, J]]
+[[Category: Hou J]]
-[[Category: Ke, H]]
+[[Category: Ke H]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]
-[[Category: Pde9a]]

4gh6

From Proteopedia

Revision as of 06:56, 26 October 2022

Crystal structure of the PDE9A catalytic domain in complex with inhibitor 28

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox